Publications

In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state.

Written and published by Biogerontology Research Foundation staff in collaboration with
Insilico Medicine Inc., Pathway Pharmaceuticals, Ltd., Center for
Biogerontology and Regenerative Medicine, Moscow Institute of Physics and
Technology, University of Tennessee Health Science Center (Department of Genetics,
Genomics, and Informatics), D. Rogachev Federal Research and Clinical Center
for Pediatric Hematology, Oncology, and Immunology, Life Extension, George
Mason University (School of Systems Biology), and the Engelhardt Institute of
Molecular Biology of Russian Academy of Sciences.

Abstract: Populations in developed nations
throughout the world are rapidly aging, and the search for geroprotectors, or
anti-aging interventions, has never been more important. Yet while hundreds of
geroprotectors have extended lifespan in animal models, none have yet been
approved for widespread use in humans. GeroScope is a computational tool that
can aid prediction of novel geroprotectors from existing human gene expression
data. GeroScope maps expression differences between samples from young and old
subjects to aging-related signaling pathways, then profiles pathway activation
strength (PAS) for each condition. Known substances are then screened and
ranked for those most likely to target differential pathways and mimic the
young signalome. Here we used GeroScope and shortlisted ten substances, all of
which have lifespan-extending effects in animal models, and tested 6 of them
for geroprotective effects in senescent human fibroblast cultures. PD-98059, a
highly selective MEK1 inhibitor, showed both life-prolonging and rejuvenating
effects. Natural compounds like N-acetyl-L-cysteine, Myricetin and
Epigallocatechin gallate also improved several senescence-associated properties
and were further investigated with pathway analysis. This work not only
highlights several potential geroprotectors for further study, but also serves
as a proof-of-concept for GeroScope, Oncofinder and other PAS-based methods in
streamlining drug prediction, repurposing and personalized medicine.